Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 2

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 2
Dr. Entisar Al Mukhtar

Pharmacokinetics:
Aspirin: orally taken aspirin is rapidly deacetylated by esterases producing salicylate. Unionized salicylates are absorbed mostly from the upper small intestine (dissolution of the tablets is favored at the gut higher pH).
Salicylates (except Diflunisal ) cross BBB and placenta and are absorbed through intact skin (especially methyl salicylate).
At anti-inflammatory dosages (more than 4 g/day), the hepatic metabolic pathway (conjugation) becomes saturated, and kinetics will shift from first-order (t ½ = 3.5 hrs) to zero-order kinetic (t ½ of 15 hrs or more). Salicylate is secreted into the urine. Low doses of aspirin ( > 2 g/day) decrease uric acid secretion, whereas at high doses, uric acid secretion may be unchanged or increased. Thus, aspirin is avoided in gout or in patients taking probenecid.
Other NSAIDs:
Well absorbed after oral administration and are highly bound to plasma proteins. Only few NSAIDs (e.g, Nabumetone & Sulindac) have active metabolites. All are eliminated via the urine.

Adverse events:
It is preferable to use NSAIDs at the lowest effective dose & for the shortest duration.
1. Gastrointestinal: ranging from dyspepsia to bleeding because normally PGI2 inhibits gastric acid secretion, and PGE2 and PGF2? stimulate protective mucus synthesis, thus COX-1 inhibitors increase gastric acid secretion, diminished mucus protection, and increased risk for GI bleeding and ulceration.
NSAIDs should be taken with food or fluids.
In patients with a high risk for GI events the proton pump inhibitors or misoprostol should be used concomitantly to prevent NSAID-induced ulcers.

2. Increased risk of bleeding (antiplatelet effect): TXA2 enhances platelet aggregation, whereas PGI2 decreases it. Aspirin irreversibly inhibits COX-1–mediated TXA2 formation. Because platelets lack nuclei, they cannot synthesize new enzyme and the lack of TXA2 persists for the lifetime of the platelet (3 to 7 days). Thus, aspirin reduce platelet aggregation & prolong bleeding time, & it is often held or not given at least 1 week prior to surgery.
Other NSAIDs are not utilized for their antiplatelet effect (because they reversibly inhibit TXA2 production) but can still prolong bleeding time. [Note: The more COX-2 selective agents have less effect on platelet inhibition.] NSAIDs can block aspirin binding to COX when used concomitantly. Patients who take aspirin for cardio- protection should avoid concomitant NSAID use if possible.

3. On kidney: NSAIDs prevent synthesis of renal blood flow maintaining PGs (PGE2 and PGI2) result in sodium and water retention and may be edema. Patients with a history of HF or kidney disease are at particularly high risk. These effects can also mitigate the beneficial effects of antihypertensive drugs.

4. Cardiac effects: NSAIDs with a very high COX-1 selectivity such as aspirin, have shown a CV protective effect due to reduction in TXA2 production.
NSAIDs with higher relative COX-2 selectivity have been associated with an increased risk for CV events, possibly by decreasing PGI2 production mediated by COX-2.
An increased risk for CV events, including MI and stroke, has been associated with all NSAIDs except aspirin.
Naproxen appears to be the least likely to be harmful for patients with CV disease.

Other side effects:
• NSAIDs should be used with caution in patients with asthma, because inhibition of PG synthesis can cause a shift toward leukotrienes production which exacerbate asthma.
• CNS (such as headache, tinnitus & dizziness).
• Hypersensitivity reactions (urticaria, bronchoconstriction, and angioedema) occurred in about 15% of patients taking aspirin. Fatal anaphylactic shock is rare.
Note: Patients with severe hypersensitivity to aspirin should avoid using NSAIDs.

Drug interactions:
Salicylate is highly (80 - 90%) bound to plasma protein (albumin) and can be displaced from protein binding sites increasing the level of free salicylate.
Also, aspirin can displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic acid .

Toxicity: mild form of salicylate intoxication (salicylism) is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness & tinnitus. Severe salicylate intoxication result in restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure may occur. As little as 10 g of aspirin can cause death in children intoxication.

Pregnancy: Most NSAIDs are pregnancy risk category C in the first 2 trimesters. [Note: Acetaminophen is a preferred analgesic or antipyretic agent during pregnancy.] In the 3rd trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus.

B. Celecoxib (other COX-2 inhibitors are Etoricoxib, Parecoxib):
• More selective inhibitor for COX-2 than COX-1.
• It cause less GI irritation than aspirin, but has a potential for increasing MI & strokes
Uses: RA, osteoarthritis, and acute mild to moderate pain.
Pharmacokinetics:
readily absorbed orally, & extensively metabolized and excreted in feces and urine. Given once or twice daily (t1/2 =11 hrs), dose should be reduced with moderate hepatic impairment, while it should be avoided with severe hepatic or renal disease.
Adverse effects:
Headache, dyspepsia, diarrhea, and abdominal pain. Less GI bleeding & dyspepsia than other NSAIDs. Patients who are at high risk of ulcers and require aspirin for CV prevention should avoid the use of celecoxib.
Like other NSAIDs, celecoxib has a similar risk for CV events.
It should be used with caution in patients who are allergic to sulfonamides. Patients with anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib.
Fluconazole & fluvastatin, may increase celecoxib serum levels.

Acetaminophen
An antipyretic & analgesic that inhibits PG synthesis in the CNS. It has weak anti-inflammatory activity because it has less effect on COX in peripheral tissues (due to peripheral inactivation), also it does not affect platelet function or bleeding time. It is not considered to be an NSAID.

Therapeutic uses
An analgesic/antipyretic NSAIDs of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin) & for patients with gastric complaints/ risks.


Pharmacokinetics
Rapidly absorbed from GIT (also available as I.V and rectal formulations).
Metabolized in the liver into inactive metabolites.
A portion of acetaminophen is metabolized in to N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive metabolite that can cause liver damage.

At normal doses (0.5 – 1g every 4-6 h, maximal daily dose 4g ) the NAPQI reacts with sulfhydryl group of glutathione in the liver, forming a nontoxic substance. Acetaminophen and its metabolites are excreted in urine.

Adverse effects
Hepatic necrosis, a very serious & potentially life threatening condition, especially in patients with hepatic disease, viral hepatitis, or a history of alcoholism. [Note: N-acetylcysteine (NAC), which contains sulfhydryl groups is given I.V as an antidote for overdose. Thus, acetaminophen should be avoided in patients with severe hepatic impairment.

Difunisal (salicylic acid derivative) cause less GI irritation than aspirin, but has no antipyretic e¬ffect.

Oxicams (Piroxicam, Meloxicam, Tenoxicam):
• Their long half-life permits daily or twice-daily dosing.
• Meloxicam is preferentially inhibits COX-2 over COX-1(10?20 fold), particularly at its lowest therapeutic dose.

Propionic acids derivatives (Ibuprofen, Fenoprofen, Flurbiprofen, Ketoprofen, Naproxen, Oxaprozin):
• All have lower toxicity than aspirin and are better acceptance in some patients.
• Naproxen has a longer half?life (13 hrs), it is considered as one of a safest NSAIDs.
• Use: Dysmenorrhea.
Fenamates (Mefenamic acid, flufenamic & meclofenamate): used for dysmenorrhea.
Acetic acids derivatives (Indomethacin, Sulindac, Tolmetin):
Indomethacin: Upper GI disturbances are common, very potent, thus should be used only after less toxic agents have proven ineffective. CNS disturbances are common.
Sulindac: a prodrug with long half-life that permits daily or twice-daily dosing